Inhibition of Dipeptidyl Peptidase-4 (DPP-4) - A Novel Approach to Treat Type 2 Diabetes

Abstract

A novel approach for treatment of type 2 diabetes is based on the gut hormone glucagon-like peptide-1 (GLP- 1), which is antidiabetic due to its combined action to stimulate insulin secretion, increase beta-cell mass, inhibit glucagon secretion, reduce the rate of gastric emptying and induce satiety. A problem is, however, that the peptide is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in a half-life of active GLP-1 of only approximately 1-2 minutes. To overcome this inconvenient drawback for the treatment of diabetes, two strategies have been successful; one strategy uses DPP-4 resistant GLP-1 receptor agonists whereas the other strategy uses inhibition of DPP-4. Such inhibition will increase the levels of endogenous active GLP-1 and prolong its half-life. The rationale behind the strategy is evident from studies in animals with genetic deletion of DPP-4, which have improved glucose tolerance and increased insulin secretion in response to oral glucose. Furthermore, in experimental animals, different pharmacological DPP-4 inhibitors are antidiabetic. Recently also studies in subjects with type 2 diabetes have shown that prolonged DPP-4 inhibition for up to 1 year is antidiabetogenic because fasting and postprandial glucose as well as HbA1c levels are reduced. This is seen in association with good tolerability and weight neutrality. Hence, DPP-4 inhibition has the potential to be a novel, efficient and tolerable approach to treat type 2 diabetes.